Computational study of cruzain enzyme by reversible covalent inhibitors

• Grant number: 18/21749-3
• Support Opportunities: Research Grants - Visiting Researcher Grant - Brazil
• Start date: January 14, 2019
• End date: January 13, 2020
• Field of knowledge: Physical Sciences and Mathematics - Chemistry
• Principal Investigator: Carlos Alberto Montanari
• Grantee: Carlos Alberto Montanari
• Visiting researcher: Jeronimo Lameira Silva
• Visiting researcher institution: Universidade Federal do Pará (UFPA). Centro de Ciências Biológicas, Brazil
• Host Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Associated research grant: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors, AP.TEM

Abstract

The prediction of the binding affinity has been a computational challenge, since binding process consists in multiple steps. In this propose, we will study the relationship between the relative biding free energy and the experimental data using computational approaches such as Free Energy Perturbation (FEP), molecular dynamics simulations and quantum mechanics/molecular mechanics (QM/MM). In addition, we will investigate the molecular inhibition mechanism of cruzain by covalent inhibitors using QM/MM. In this project, it is expected to find important information to optimize reversible covalent inhibitors that can be used for the treatment of Chagas disease. Of particular interest, we will study the reactivity of the electrophilic centers in order to modulate the reversibility of the covalent bond between the catalytic cysteine sulfur (Cys25) and the electrophilic groups (warheads).Keywords: QM/MM, FEP, cruzain inhibitors. (AU)

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BONATTO, VINICIUS; JATAI BATISTA, PEDRO HENRIQUE; CIANNI, LORENZO; DE VITA, DANIELA; SILVA, DANIEL G.; CEDRON, RODRIGO; TEZUKA, DAIANE Y.; DE ALBUQUERQUE, SERGIO; MORAES, CAROLINA BORSOI; FRANCO, CAIO HADDAD; et al. On the intrinsic reactivity of highly potent trypanocidal cruzain inhibitors. RSC MEDICINAL CHEMISTRY, v. 11, n. 11, p. 1275-1284, NOV 1 2020. (18/21749-3, 18/15904-6, 13/18009-4)

SILVA, JOSE ROGERIO A.; CIANNI, LORENZO; ARAUJO, DEBORAH; JATAI BATISTA, PEDRO HENRIQUE; DE VITA, DANIELA; ROSINI, FABIANA; LEITAO, ANDREI; LAMEIRA, JERONIMO; MONTANARI, CARLOS A.. Assessment of the Cruzain Cysteine Protease Reversible and Irreversible Covalent Inhibition Mechanism. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 60, n. 3, p. 1666-1677, MAR 23 2020. (13/18009-4, 18/21749-3)

DA COSTA, CLAUBER H. S.; BONATTO, VINICIUS; DOS SANTOS, ALBERTO M.; LAMEIRA, JERONIMO; LEITAO, ANDREI; MONTANARI, CARLOS A.. Evaluating QM/MM Free Energy Surfaces for Ranking Cysteine Protease Covalent Inhibitors. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 60, n. 2, p. 880-889, FEB 2020. (13/18009-4, 18/21749-3)

LAMEIRA, JERONIMO; BONATTO, VINICIUS; CIANNI, LORENZO; ROCHO, FERNANDA DOS REIS; LEITAO, ANDREI; MONTANARI, CARLOS A.. Predicting the affinity of halogenated reversible covalent inhibitors through relative binding free energy. Physical Chemistry Chemical Physics, v. 21, n. 44, p. 24723-24730, NOV 28 2019. (13/18009-4, 18/21749-3)

DOS SANTOS, ALBERTO M.; SANTANA OLIVEIRA, AMANDA RUSLANA; DA COSTA, CLAUBER H. S.; KENNY, PETER W.; MONTANARI, CARLOS A.; VARELA, JALDYR DE JESUS G.; LAMEIRA, JERONIMO. Assessment of Reversibility for Covalent Cysteine Protease Inhibitors Using Quantum Mechanics/Molecular Mechanics Free Energy Surfaces. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 62, n. 17, p. 12-pg., 2022-09-12. (18/21749-3, 13/18009-4)